Cells contain a blueprint in the form of DNA that dictates what they can make.
This blueprint is converted into a message, or mRNA, which is then converted into protein.
Although DNA remains the same in all cells, how it is read depends on specific signals that can change the DNA itself, mRNA or proteins.
These signals are often in the form of chemical modifications.
In a study published in Stem Cell Reports, researchers from the University of Michigan investigated which signals control the development of stem cells into retinal cells .
Their findings could help inform future research into creating cells for transplantation and screening promising drugs for retinal diseases.
Cells can control the types of proteins they make by adding different types of chemical groups onto DNA and RNA.
These include molecules called methyl groups that destabilize RNA. The lifetime of RNA, in turn, controls how much protein can be made.
"Chemical modifications to RNA have been studied in other areas, including diabetes and cancer," said Rajesh C. Rao, M.D., Leonard G. Miller Professor of Ophthalmology and Visual Sciences and an associate professor of pathology and human genetics.
"However, no one had looked at how they affect the process by which stem cells turn into retinal cells."
In the study, the researchers focused on METTL3, a protein which adds methyl groups to RNA.
Using genetic tools, they looked at the consequences of deleting METTL3 or modifying it so that it cannot add methyl groups.
They found that METTL3 needs to be in the nucleus to drive the formation of retinal cells.
The team then mapped all the regions on the RNA that are modified by METTL3 using a technique called GLORI.
They integrated mapping information with RNA engineering to remove RNA modifications for the gene Six3, which controls stem cell-to-retina formation.
They found that RNA modifications regulated Six3 RNA stability.
Using a CRISPR system specific to RNA, they found that modifications on one end of the RNA, known as the 3' end, were important in regulating stability of RNA of the Six3 gene.
They also found that inhibiting the expression of the Ythdf family of genes had a similar blocking effect of stem cells-to-retina as did METTL3 loss.
"This is the first report to look at the mechanisms of RNA epigenetics, or how chemical modifications in RNA can influence the process of stem cells development into retinal tissue," Rao said.
The team is studying how METTL3 changes RNA without affecting the shape of DNA, a surprising discovery they made during the study.
They're also interested in understanding whether these RNA modifications are affected during retinal diseases.
"We know that the RNA modifications are affected by high sugar," Rao said.
"The retina is a very sensitive tissue and can get damaged quite easily in patients with diabetes and we want to understand whether RNA modifications are involved."
Additional authors: Jing Xu, Yuanhao Huang, Zhaowei Han, Qiang Li and Jie Liu.
Funding/disclosures: The study was supported by the National Eye Institute (R01EY030989), Research to Prevent Blindness Career Advancement and Unrestricted Departmental Awards, A. Alfred Taubman Medical Research Institute, the Beatrice and Reymont Paul Foundation, March Hoops to Beat Blindness, and Leonard G. Miller Endowed Professorship and Ophthalmic Research Fund at the Kellogg Eye Center. Additional support for this research was provided by Grossman, Elaine Sandman, Marek and Maria Spatz, Greenspon, Dunn, Avers, Boustikakis, Sweiden and Terauchi research funds. The University of Michigan Vision Research Center (P30EY007003) provided some Core Services. Liu was supported by the National Institute of General Medical Sciences (R35HG011279).
Paper cited: "METTL3 Uncouples Chromatin Accessibility from Transcription during Retinal Development," Stem Cell Reports. DOI: 10.1016/j.stemcr.2025.102690
